Over the past decade, mechanical means of achieving revascularization of obstructive atherosclerotic vessels have been greatly improved. Percutaneous transluminal coronary angioplasty (PTCA) procedures include, but are not limited to, balloon dilatation, excisional atherectomy, endoluminal stenting, rotablation and laser ablation. However, revascularization induces thrombosis, and neointimal hyperplasia, which in turn cause restenosis in a substantial proportion of coronary arteries after successful balloon angioplasty and in aortacoronary saphenous vein bypass graft and other coronary grafts. Furthermore, intimal hyperplasia causes restenosis in many superficial femoral angioplasties, carotid endarterectomies, and femoro-distal vein bypasses. Restenosis is the formation of new blockages at the site of the angioplasty or stent placement or the anastomosis of the bypass. As a result, the patient is placed at risk of a variety of complications, including heart attack or other ischemic disease, pulmonary embolism, and stroke. Thus, such procedures can entail the risk of precisely the problems that its use was intended to ameliorate. The introduction of endovascular stents has reduced the incidence of restenosis, but this problem still remains significant, since restenosis or “over exuberant” tissue healing may occur at the site of stent placement. (Waller, B. F. et al., 1997, Clin-Cardiol., 20(2):153-60; Anderson, W. D et al., 1996, Curr-Opin-Cardiol., 11(6):583-90; Moorman, D. L. et al., 1996, Aviat-Space-Environ-Med., 67(10):990-6; Laurent, S. et al., 1996, Fundam. Clin. Phamacol. 10(3):243-57; Walsh, K. et al., 1996, Semin-Interv-Cardiol., 1(3):173-9; Schwartz, R. S., 1997, Semin-Interv-Cardiol., 2(2):83-8; Allaire, E. et al., 1997, Ann. Thorac. Surg., 63:582-591; Hamon, M. et al., 1995, Eur. Heart J., 16:33s-48s; Gottsauner-Wolf, M., et al., 1996, Clin. Cardiol., 19:347-356).
Despite extensive research on the incidence, timing, mechanisms and pharmacological interventions in humans and animal models to date, no therapy exists which consistently prevents coronary restenosis (Herrman, J. P. R. et al., 1993, Drugs, 46:18-52; Leclerc, G. et al., 1995, Elsevier Science, 722-724, Topol, E., 1997, The NY Academy of Sciences, 225-277). Compositions and methods for the reduction or prevention of restenosis are still greatly desired. Accordingly, it would be desirable to develop novel compositions and methods that are effective in treating restenosis and preventing its reoccurrence.
Bisphosphonates (“BPs”) (formerly called diphosphonates) are compounds characterized by two C—P bonds. If the two bonds are located on the same carbon atom (P—C—P) they are termed geminal bisphosphonates. The BPs are analogs of the endogenous inorganic pyrophosphate which is involved in the regulation of bone formation and resorption. The term bisphosphonates is generally used for geminal and non-geminal bisphosphonates. The BPs may at times form polymeric chains. BPs act on bone because of their affinity for bone mineral and also because they are potent inhibitors of bone resorption and ectopic calcification. BPs have been clinically used mainly as (a) antiosteolytic agents in patients with increased bone destruction, especially Paget's disease, tumor bone disease and osteoporosis; (b) skeletal markers for diagnostic purposes (linked to 99mTc); (c) inhibitors of calcification in patients with ectopic calcification and ossification, and (d) antitartar agents added to toothpaste (Fleisch, H., 1997, in: Bisphosphonates in bone disease. Parthenon Publishing Group Inc., 184-186). Furthermore, being highly hydrophilic and negatively charged, BPs in their free form are almost incapable of crossing cellular membranes.